Oral Treatment for Mycobacterium ulcerans Infection: Results From a Pilot Study in Benin

Mycobacterium ulcerans infection is responsible for severe skin lesions in sub-Saharan Africa. We enrolled 30 Beninese patients with Buruli ulcers in a pilot study to evaluate efficacy of an oral chemotherapy using rifampicin plus clarithromycin during an 8-week period. The treatment was well tolerated, and all patients were healed by 12 months after initiation of therapy without relaps

Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study

Background Buruli ulcer, caused by Mycobacterium ulcerans, was identifi ed as a neglected emerging infectious disease by WHO in 1998. Although Buruli ulcer is the third most common mycobacterial disease worldwide, understanding of the disease is incomplete. We analysed a large cohort of laboratory-confi rmed cases of Buruli ulcer from Pobè, Benin, to provide a comprehensive description of the clinical presentation of the disease, its variation with age and sex, and its eff ect on the occurrence of permanent functional sequelae. Methods Between Jan 1, 2005, and Dec 31, 2011, we prospectively collected clinical and laboratory data from all patients with Buruli ulcer diagnosed at the Centre de Dépistage et de Traitement de l’Ulcère de Buruli in Pobè, Benin. We followed up patients to assess the frequency of permanent functional sequelae. All analyses were done on cases that were laboratory confi rmed. Findings 1227 cases of laboratory-confi rmed Buruli ulcer were included in the analysis. Typically, patients with Buruli ulcer were children (median age at diagnosis 12 years) presenting with a unique (1172 [96%]) large (≥15 cm, 444 [36%]) ulcerative (805 [66%]) lesion of the lower limb (733 [60%]). Atypical clinical presentation of Buruli ulcer included Buruli ulcer osteomyelitis with no identifi able present or past Buruli ulcer skin lesions, which was recorded in at least 14 patients. The sex ratio of Buruli ulcer widely varied with age, with male patients accounting for 57% (n=427) of patients aged 15 years and younger, but only 33% (n=158) of those older than 15 years (odds ratio [OR] 2·59, 95% CI 2·04–3·30). Clinical presentation of Buruli ulcer was signifi cantly dependent on age and sex. 54 (9%) male patients had Buruli ulcer osteomyelitis, whereas only 28 (4%) of female patients did (OR 2·21, 95% CI 1·39–3·59). 1 year after treatment, 229 (22% of 1043 with follow-up information) patients presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was signifi cantly associated with occurrence of permanent functional sequelae (OR 7·64, 95% CI 5·29–11·31) and operationally defi nes severe Buruli ulcer. Interpretation Our fi ndings have important clinical implications for daily practice, including enhanced surveillance for early detection of osteomyelitis in boys; systematic search for M ulcerans in osteomyelitis cases of non-specifi c aspect in areas endemic for Buruli ulcer; and specifi c disability prevention for patients presenting with osteomyelitis, oedema, or multifocal or large lesions. Our fi ndings also suggest a crucial underestimation of the burden of Buruli ulcer in Africa and raise key questions about the contribution of environmental and physiopathological factors to the recorded heterogeneity of the clinical presentation of Buruli ulcer

Defining and targeting high-risk populations in Buruli ulcer–Authors' reply

International audienceWe thank Jordi Landier and colleagues for their comments about our recent Article in The Lancet Global Health. 1 In their work, Landier and coworkers generalise some of our observations on Buruli ulcer in Benin to those for Cameroon, the country that has the fifth highest prevalence of Buruli ulcer worldwide. Briefly, they make use of age and sex distribution from the Cameroon national census to show that patients aged 5–14 years were twice as likely to be affected by Buruli ulcer as older individuals; and that boys were over-represented in individuals younger than 15 years, women were over-represented in patients aged 15–50 years, and that men and women were equally represented in patients older than 50 years. They advocate the use of national census references to produce incidence rates and incidence rate ratios (IRRs), which they believe to be the proper way to draw valid conclusions.</p

Clinical presentation of lesions (Patient 1).

<p>A: Initial ulcerated lesion at the right arm, reaching from the elbow to the forearm. B: Nodule1 appearing on the back, 275 days after end of antibiotic treatment. Both, nodule 2 on the thorax (C) and an ulcerated plaque on the right shoulder (D) had appeared 409 days after completion of antibiotic treatment.</p

Presence of B-cell clusters in the secondary lesions.

<p>A: Band of CD20 positive B-cells in sections of ulcer 2 of patient 1. B–E: serial sections of nodule 3 of patient 2 with a small dense cluster of CD20 positive B-cells (B) surrounded by CD14 positive macrophages/monocytes (C) and few interspersed CD3 positive T-cells (D) from which the majority was CD8 negative (E). Higher magnification (F–I) revealed a very dense package of the B-cells.</p

Bands of leucocytes surrounding an uninfiltrated necrotic area.

<p>Serial sections of nodule 2 of patient 1 with a necrotic area surrounded by a belt of CD14 positive monocytes/macrophages (A) and a more external second belt of CD3 positive T-cells (B). The necrotic core contained N-elastase positive neutrophilic debris (C), but no intact neutrophils (D insert). Clusters of CD20 positive B-cells were found away from the necrotic core (D).</p

Histopathological presentation of secondary lesions.

<p>Histological sections (nodule 2 of patient 2) were stained either with Ziehl-Neelsen (counterstain methylenblue; A, F, G) or with antibodies against cell surface or cytoplasmic markers (counterstain haematoxylin; B–E). A: Overview over excised tissue specimen revealing typical BU pathology features like fat cell ghosts, necrosis, epidermal hyperplasia and AFB (region 2) as well as a strong mixed infiltration typically observed in successfully treated BU lesions (region 1). B: CD14 staining of macrophages/monocytes; C: CD3 staining of T-cells; D: Elastase staining of neutrophils. In the necrotic region 2 large numbers of elastase-positive neutrophilic debris (E) and small clumps of AFB (F) with a beaded appearance (G) were observed.</p

Promising Clinical Efficacy of Streptomycin-Rifampin Combination for Treatment of Buruli Ulcer (Mycobacterium ulcerans Disease)▿

According to recommendations of the 6th WHO Advisory Committee on Buruli ulcer, directly observed treatment with the combination of rifampin and streptomycin, administered daily for 8 weeks, was recommended to 310 patients diagnosed with Buruli ulcer in Pobè, Bénin. Among the 224 (72%) eligible patients for whom treatment was initiated, 215 (96%) were categorized as treatment successes, and 9, including 1 death and 8 losses to follow-up, were treatment failures. Of the 215 successfully treated patients, 102 (47%) were treated exclusively with antibiotics and 113 (53%) were treated with antibiotics plus surgical excision and skin grafting. The size of lesions at treatment initiation was the major factor associated with surgical intervention: 73% of patients with lesions of >15 cm in diameter underwent surgery, whereas only 17% of patients with lesions of <5 cm had surgery. No patient discontinued therapy for side effects from the antibiotic treatment. One year after stopping treatment, 208 of the 215 patients were actively retrieved to assess the long-term therapeutic results: 3 (1.44%) of the 208 retrieved patients had recurrence of Mycobacterium ulcerans disease, 2 among the 107 patients treated only with antibiotics and 1 among the 108 patients treated with antibiotics plus surgery. We conclude that the WHO-recommended streptomycin-rifampin combination is highly efficacious for treating M. ulcerans disease. Chemotherapy alone was successful in achieving cure in 47% of cases and was particularly effective against ulcers of less than 5 cm in diameter

Features of skin lesions that emerged after completion of antibiotic treatment.

<p>Lesions from which tissue samples became available for histopathological analysis are written in bold letters.</p